1. Field of the Invention
The present invention relates to a once a daily extended release oral Tramadol pharmaceutical preparation which provides effective blood concentration for a period of about 24 hours with reduced peak Tramadol plasma concentrations. The formulation of the present invention provides peak Tramadol plasma concentration s that are less than twice three times the plasma concentration measured 24 hours after administration, while providing for effective Tramadol plasma concentration about 1 to 2 hours after administration.
2. Description of the Background
Tramadol is a centrally acting synthetic analgesic compound that is not derived from natural sources nor is it chemically related to opiates. Although its mode of action is not completely understood, at least two complementary mechanisms appear applicable: Binding to μ-opioid receptors and inhibition of reuptake of nor epinephrine and serotonin. Tramadol opioid activity derives from low affinity binding the parent compound to A-opioid receptors and higher affinity binding of the M1 metabolite. In animal models, M1 is up to 6 times more potent than Tramadol in producing analgesia and 200 times more potent in u-opioid binding. The contribution to human analgesia of Tramadol relative to M1 is unknown.
Tramadol-induced antinociception is only partially antagonized by the opiate antagonist naloxone in animal test. In addition, Tramadol inhibits reuptake of nor-epinephrine and serotonin in-vitro after oral administration of immediate release dosage form the onset of analgesia is evident within 1 hour after administration and reaches a peak in ≈2 to 3 hours. Peak plasma concentrations are reached about 2 hours after administration, which correlates closely with the time to peak pain relief.
Tramadol immediate release is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of 100 mg oral dose is ≈75%. Administration with food does not significantly affect its rate or extent of absorption; therefore, it can be administered without regard to meals. The mean peak plasma concentration is 308±78 ng/ml and occurs at ≈2 hours after a single 100 mg oral dose in healthy subjects. At this dose, the mean peak plasma concentration of the active mono-O-desmethyl metabolite (racemic 1) is 55±20 ng/ml and occurs ≈3 hours post-dose. The separate [+]- and [−]-enantiomers of Tramadol generally follow a parallel time course in plasma after a single 100 mg oral dose. Following a 100 mg dose, the maximum plasma concentrations of the [−]-enantiomers are some-what lower than those of the [+]-enatiomer (148±33 vs. 168±36 ng/ml, respectively), The [−]-M1 enantiomer (35±10 vs, 26±13 ng/ml, respectively). Steady state is achieved after 2 days of a 100 mg four times daily dosing regimen (maximum plasma concentration was 592±177 ng/ml). The plasma half-life of Tramadol, following single and multiple dosing, was 6 and 7 hours, respectively. The most common adverse reaction is nausea, vertigo, constipation and headaches and is correlated to the patients plasma Tramadol concentrations.
Tramadol is used for the management of moderate to moderately severe pain such as pain following surgical procedures (orthopedic, gynecological cesarean section) and pain following dental surgery (extraction of impacted molars).
Tramadol ability to control pain is directly related to its concentration in the patient's plasma stream. The minimum effective therapeutical Tramadol plasma level is around 100 ng/ml. Due to Tramadol plasma elimination short half-life to maintain the minimum effective plasma levels requires generally the oral administration of 50 to 100 mg every 4 to 6 hours of immediate release Pharmaceutical compositions. This administration schedule of the drug makes it difficult for the patient to control pain, specially during night time, since pain will reappear every 4 to 6 hours.
On the other hand, if patient in an attempt to control pain for a longer period of time should take higher doses of immediate release Tramadol than peak plasma levels will increase dramatically and very serious side effects due to high blood levels will appear immediately.
Another difficulty encountered by the man skilled in the art for the production of a once daily Tramadol formulation arises from Tramadol extremely high solubility in water and body fluids. The prior art teaching related to Tramadol compositions that may be useful for once daily administration are basically related to maintain effective therapeutically plasma concentrations between administration. Since it is known the therapeutically effective Tramadol plasma levels are close to the unwanted adverse reaction plasma levels, once a day Tramadol compositions to be useful to treat effectively patients in need must not only provide for minimum effective therapeutic plasma levels but also must provide for the control of toxic levels. Any once a day Tramadol formulation which should not comply with both requirements would be useless.
U.S. Pat. No. 5,601,842 discloses a tablet containing Tramadol and a matrixing agent with a viscosity between 3,000 and 150,000 mPa in a 2% aqueous solution at 20° C. U.S. Pat. No. 5,811,126 discloses a controlled release pharmaceutical composition containing Tramadol and comprising sodium alginate, C2 to C50, edible hydrocarbon derivative with melting point range from 25° C. to 90° C. and divalent salt to cross link the alginate. In vivo performance from these formulations is not available.
U.S. Pat. Nos. 5,639,476 (12h) and 5,580,578 discloses controlled release dosage form containing a substrate containing Tramadol, said substrate being coated with a plasticized aqueous dispersion of ammonio-methacrylate copolymer having low content of quaterny ammonium groups and a permeability enhancing pore former said coating being cured for about 24 to about 60 hours to stabilize said formulation.
U.S. Pat. No. 5,955,104 discloses a delayed release Tramadol formulation consisting of pellets in a water soluble capsule or in a tablet compressed from said pellets, each pellet having (a) a substantially inert core; (b) an active ingredient layer containing (i) Tramadol particles in mixture with a binder for adhering said Tramadol particles over said inert core, and optionally (iii) a pharmaceutically acceptable, inner adjuvant; and (c) a delay coating for retarding the release of Tramadol consisting principally of mixtures of Ethylcellulose and shellac.
U.S. Pat. Nos. 5,645,858, 5,474,786 and 5,395,626 discloses multilayered controlled release pharmaceutical dosages forms for water soluble drugs comprising a plurality of coated beads and which comprises a core and seven or eight different coatings.
U.S. Pat. No. 5,849,240 describes a process for the manufacture of particles by the “melt-pelletization” process, Tramadol is one of the examples but in vivo performances of such formulation is not available.
US Pat. No. 5,968,551 (continuation of patent 5,273,760) describes sustained release oral analgesic form for once a day administration comprising a unit dose comprising a plurality of pharmaceutical acceptable matrices comprising an analgesically effective amount of Tramadol and hydrophobic material each of said matrices having a diameter of about 0.1 to 3 mm bioavailability and therapeutical effect for about 24 hours or more after oral administration to a human patient (no control of side effects). It also discloses a method of treating patients for moderate to severe pain with a once daily oral administration of a unit dose consisting of a plurality of inert pharmaceutical acceptable beads control with an analgesically effective amount of an opioid analgesic said beads having a diameter of 0.1 to 3 mm and having effective blood levels for about 24 hours (against side effects) with a peak of said opioid in vivo for about 3 to about 10 hours after administration.
U.S. Pat. No. 5,965,163 describes a solid dosage form comprising a plurality of particles including Tramadol in a matrix, the matrix including a mixture of hydrophobic and hydrophilic fusible carriers having melting point from 35° C. to 150° C., which are produced by the method of “melt pelletization”.
US Pat. No. 5,591,452 disclosures a once daily Tramadol preparation constituted of Tramadol incorporated into a controlled release matrix constituted of one or more hydrophilic or hydrophobic polymers which provides a Tmax of about 3 to about 6 hours.
U.S. Pat. No. 5,958,482 describes a sustained release pharmaceutical formulation comprising an extruded blend of Tramadol, and one or more hydrophobic fusible carriers having a melting point from about 300 to about 200° C., providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours. With a peak plasma for about 2 to 8 hours.
U.S. Pat. No. 5,891,471 discloses Tramadol pharmaceutical particles for once a day administration which provides a time to peak plasma level of Tramadol in about 2 to about 6 hours after administration, produced by a process of “melt-pelletization”.
U.S. Pat. Nos. 5,672,360 and 5,478,577 discloses a method of treating pain in humans comprising orally administering of a once a day basis an oral sustained release dosage form of an opioid analgesic which upon single dose and multiple doses administration provides a time to maximum plasma concentration (Tmax) of said opioid in about 2 to 10 hours and a maximum plasma concentration (Cmax) which is more than twice the plasma level of said opioid at about 24 hours after administration of the dosage form and which dosage form provides effective treatment of pain for about 24 hours or more after administration to the patient.
An orally administrable Tramadol formulation for once a day administration, which would provide effective Tramadol plasma concentrations without Tramadol plasma peaks would be highly desirable.
A pharmaceutical oral dosage formulation of Tramadol a) providing rapidly effective plasma concentration and b) able to maintain such effectives plasma concentration for a long period of time while simultaneously avoiding peak Tramadol blood concentrations would be highly desirable to provide an immediate and extended duration of analgesia with low incidence of adverse effects to patients in pain.
The Tramadol (or salt) once daily composition of the present invention permit the rapid obtention of Tramadol effective plasma concentration, within one or two hours which are maintained for a period of about 24 hours while providing for peak Tramadol blood concentration which are less than free times the concentration obtained twenty four hours after administration.